Abstract: At present, pancreatic ductal adenocarcinama (PDAC) is one of the deadliest malignant solid tumors, with poor prognosis and 5-year survival rate of 5%. Although understanding of the pathogenesis has greatly been improved for nearly two decades, there isn't a breakthrough in clinical therapy of the PDAC, and finding a new and effective therapy is badly needed. Genetic analysis showed that KRAS was one of the earliest and great probability mutated gene in the PDAC, played a significant role in initiation, progression, and metastasis of cancer, and predicted to being a good target of anti-PDAC. But a KRAS-targeted effective drug is lacking in clinic. The direct KRAS-targeted therapy will bright prospects. Meanwhile, locking localization and activity of cell membrane through post-translational modifications to KRAS combined with inhibiting KRAS downstream pathway is a good way of the KRAS-targeted PDAC therapy.